Skip to main content

Prediction of pathologic complete response after single-dose MR-guided partial breast irradiation in low-risk breast cancer patients: the ABLATIVE-2 trial—a study protocol



Partial breast irradiation (PBI) is standard of care in low-risk breast cancer patients after breast-conserving surgery (BCS). Pre-operative PBI can result in tumor downstaging and more precise target definition possibly resulting in less treatment-related toxicity. This study aims to assess the pathologic complete response (pCR) rate one year after MR-guided single-dose pre-operative PBI in low-risk breast cancer patients.


The ABLATIVE-2 trial is a multicenter prospective single-arm trial using single-dose ablative PBI in low-risk breast cancer patients. Patients ≥ 50 years with non-lobular invasive breast cancer ≤ 2 cm, grade 1 or 2, estrogen receptor-positive, HER2-negative, and tumor-negative sentinel node procedure are eligible. A total of 100 patients will be enrolled. PBI treatment planning will be performed using a radiotherapy planning CT and -MRI in treatment position. The treatment delivery will take place on a conventional or MR-guided linear accelerator. The prescribed radiotherapy dose is a single dose of 20 Gy to the tumor, and 15 Gy to the 2 cm of breast tissue surrounding the tumor. Follow-up MRIs, scheduled at baseline, 2 weeks, 3, 6, 9, and 12 months after PBI, are combined with liquid biopsies to identify biomarkers for pCR prediction. BCS will be performed 12 months after radiotherapy or after 6 months, if MRI does not show a radiologic complete response. The primary endpoint is the pCR rate after PBI. Secondary endpoints are radiologic response, toxicity, quality of life, cosmetic outcome, patient distress, oncological outcomes, and the evaluation of biomarkers in liquid biopsies and tumor tissue. Patients will be followed up to 10 years after radiation therapy.


This trial will investigate the pathological tumor response after pre-operative single-dose PBI after 12 months in patients with low-risk breast cancer. In comparison with previous trial outcomes, a longer interval between PBI and BCS of 12 months is expected to increase the pCR rate of 42% after 6–8 months. In addition, response monitoring using MRI and biomarkers will help to predict pCR. Accurate pCR prediction will allow omission of surgery in future patients.

Trial registration

The trial was registered prospectively on April 28th 2022 at (NCT05350722).

Peer Review reports


Over the last decades, the introduction of breast cancer screening and the implementation of digital mammography and MRI have resulted in an increased incidence of early-stage breast cancer. The incidence will continue to increase due to the growth and aging of the population and the increasing prevalence of risk factors across the world [1, 2]. Additionally, by scaling up traditional treatment and imaging modalities, the global 5-year net survival is estimated to rise from 67.9% to 78.2% [3]. Both trends result in an ongoing increase in the absolute number of breast cancer patients, for example from 3.9 million in 2019 to an expected 5.0 million in 2030 in the United States [4]. At the same time, there is a shift towards personalized and less invasive therapies aiming to decrease treatment-associated toxicity and to improve cosmetic results and quality of life of patients without compromising oncological safety. The most applied standard treatment for early-stage breast cancer is breast-conserving surgery (BCS) followed by whole breast irradiation (WBI) [5, 6]. However, the majority of ipsilateral breast tumor recurrences (IBTR) occur at or in the vicinity of the primary tumor site [7]. Therefore, partial breast irradiation (PBI), in which only the tumor bed is irradiated, has recently become standard treatment for low-risk patients [8]. In general, patients are eligible for PBI when they meet the American Society of Radiation Oncology (ASTRO) or the European Society for Radiation Oncology (ESTRO) suitable criteria [9, 10].

Postoperative PBI leads to a smaller irradiated breast volume, reduced radiotherapy-associated toxicity, and similar 5-year (0.5% vs. 1.1%) and 10 year (3.7% vs. 2.5%) IBTR rates compared to WBI [11, 12]. Nevertheless, postoperative PBI remains challenging as delineation of the tumor bed can be difficult, due to distortion of the breast and postoperative seroma in the surgical cavity, resulting in unnecessarily large irradiated volumes. In contrast to postoperative tumor bed delineation, pre-operative tumor delineation allows more precise target delineation with less interobserver variation between radiation oncologists, and smaller irradiated volumes since the tumor is still in situ [13,14,15,16]. As a result, radiotherapy-associated toxicity could be reduced and quality of life improved. Additionally, pre-operative PBI allows a higher radiotherapy (RT) dose per fraction due to the smaller target volume, thereby allowing ultra-hypofractionation to ultimately one single dose, and reducing treatment burden.

Pre-operative external beam PBI has previously been investigated in patients with low-risk breast cancer [17,18,19,20,21,22,23,24]. These studies showed excellent oncological outcomes with local recurrence in 0–3% of the patients and overall survival of 97–100% after a follow-up of 21 to 60 months [19, 21, 23]. Acute and late toxicity was mild to moderate in the majority of patients [17, 19,20,21,22,23]. Cosmetic outcomes reported by both patients and physicians were good to excellent in respectively 78–100% and 89–100% of the patients [19,20,21,22,23]. In the ABLATIVE study (NCT02316561), which preceded the current study, pathologic complete response (pCR) was achieved in 42% of the patients at 6 to 8 months after single-dose ablative pre-operative PBI [21]. This was higher compared to other studies that evaluated pCR after single-dose pre-operative PBI, potentially due to the longer interval between RT and BCS [17, 18, 20, 25].

Response monitoring using MRI is standard clinical practice in patients treated with pre-operative systemic therapy [26, 27]. After pre-operative RT, data on radiologic response on MRI or other imaging are limited. Two studies showed that a radiologic complete response (rCR) on MRI had a positive predictive value (PPV) for pCR of 67–88% and negative predictive value (NPV) of 76–85% after pre-operative PBI [21, 28]. This means that a significant proportion of patients with rCR on MRI still have residual tumor in the surgical specimen. In the ABLATIVE trial, 67% of patients with rCR had a pCR and 33% had near pCR after 6 to 8 months [21]. Additionally, the prediction of pCR after pre-operative systemic therapy using liquid biopsies and biomarkers in tumor tissue, such as tumor-infiltrating lymphocytes (TILs), have been evaluated, and to a much lesser extent after pre-operative RT [21, 29,30,31]. The ABLATIVE trial showed presence of TILs pre-irradiation and 6 to 8 months post-irradiation [29]. No significant difference in the number of pre-irradiation TILs was observed in responders and non-responders treated with pre-operative PBI. Consequently, more data is needed to establish the predictive value of biomarkers and to develop prediction models for pathologic response in patients treated with pre-operative RT. If pCR can be more accurately predicted after pre-operative PBI in the future, surgery could be omitted in these low-risk patients. In future patients without a pCR, single-dose pre-operative PBI could replace multiple fractionated post-operative radiotherapy, and tumor downstaging could lead to excision of less healthy breast tissue.

The ABLATIVE-2 trial aims to assess the rate of pCR in low-risk breast cancer patients treated with MR-guided single-dose pre-operative PBI. In addition, radiologic response on MRI, toxicity, oncological outcomes, cosmetic outcomes, quality of life, liquid biopsies, and immune response markers in blood and tumor tissue will be evaluated before and after pre-operative PBI.


Study design

The ABLATIVE-2 trial is a Dutch multicenter, phase II, single-arm prospective study at the Radiotherapy Departments of the Amsterdam University Medical Centres (UMC) and Radboudumc in the Netherlands. Eligible patients are treated with MR-guided pre-operative PBI. BCS will be performed at 12 months post-PBI. Between RT and surgery, tumor response is monitored using MRI at 2 weeks, 3, 6, 9 and 12 months, and compared with the baseline MRI (before PBI). In case of tumor progression on MRI at any time or when residual tumor at 6 months is suspected, BCS is performed immediately (within two to four weeks). The primary objective of this study is to determine the rate of pCR one year after single-dose ablative RT and BCS in patients with early-stage breast cancer. The secondary objectives are to evaluate the radiologic response on MRI, radiotherapy- and surgery-induced toxicity, cosmetic outcome, and patients’ quality of life and distress. The oncological outcomes: local, regional, and distant relapse rates and overall survival will be assessed. Liquid biopsies and immune response markers in blood and tumor tissue pre- and post-RT will be evaluated. All tumor tissue and blood samples of patients will be preserved at the Amsterdam UMC Central Biobank, location Vrije Universiteit Medical Center (VUmc).

Study population

Patients are eligible if they have histologically confirmed invasive breast cancer with low-risk characteristics according to the suitable criteria of the ASTRO guidelines for PBI [9, 10]. Low-risk criteria in this trial are women of 50 years or older with a cT1N0 non-lobular tumor, Bloom and Richardson grade 1 or 2, hormone receptor-positive, and HER2-negative. The inclusion and exclusion criteria are summarized in Table 1 [9].

Table 1 Inclusion and exclusion criteria for the ABLATIVE-2 trial

Study outcomes

The primary endpoint is the rate of patients with pCR one year after single-dose pre-operative RT treatment. Secondary endpoints are the time to rCR on MRI and the correlation between radiologic and pathologic response. In addition, radiotherapy- and surgery-induced toxicity will be assessed according to the Common Toxicity Criteria Adverse Events version 5.0 [32]. Patient-reported outcome measures will be assessed using the European Organization for Research and Treatment of Cancer core-30 (EORTC-QLQ-C30) and breast cancer-specific (QLQ-BR23) quality of life questionnaires and the Hospital Anxiety and Depression Scale (HADS) questionnaire. Cosmetic outcome is assessed by the patient using the BREAST-Q questionnaire. The radiation oncologist rates the cosmetic outcome as excellent, good, fair, and poor, based on breast changes such as telangiectasia and fibrosis. Cosmetic evaluation is also performed objectively using imaging captured by the VECTRA XT 3D-imaging system (Canfueld Sci, New Jersey, USA). Oncological outcomes are assessed using local, regional and distant relapse rates, and disease-free and overall survival since RT. Additionally, liquid biopsies and radiotherapy-associated immune response markers in blood and pre- and post-RT tumor tissue are investigated. The time points for the evaluation of outcomes are displayed in Fig. 1.

Fig. 1
figure 1

Overview of outcome measurements. Time points counted from radiotherapy treatment. Legend: w weeks, m months, y years. *questionnaires include evaluation of cosmetic outcomes and quality of life


In Fig. 2 an overview of all study procedures in the ABLATIVE-2 trial is shown. The dedicated breast surgeon or breast cancer nurse will inform the patient during consultation on the possibility of participation in a trial evaluating pre-operative single-dose RT with delayed surgery. If the patient is interested in trial participation, written study information is handed over and additional information is given by the physician-researcher. This is followed by a referral for pre-operative consultation with the dedicated breast radiation oncologist.

Fig. 2
figure 2

Overview study design. *Additional consent required

Diagnostic workup

After informed consent, several procedures are required to confirm that the patient meets the eligibility criteria. First, a diagnostic MRI with perfusion and diffusion sequences in prone position is performed to exclude tumor multifocality or multicentricity and to assess tumor diameter. If no marker has been inserted in the tumor during the diagnostic biopsy, the radiologist will place an MRI-compatible marker in the tumor. Since pre-operative treatment will lead to tumor downstaging, a marker is mandatory for tumor localization during excision. After separate additional consent, extra tumor biopsies will be performed and stored in the Biobank. Secondly, the surgeon will perform a sentinel node procedure using technetium-99 m-nanocolloid, to rule out nodal involvement.

Treatment planning

Besides the standard radiotherapy planning CT in the treatment position, a planning MRI scan will be performed in treatment position. The gross tumor volume (GTV), which is the breast tumor on the diagnostic MRI, will be delineated on the planning MRI by a radiation oncologist specialized in breast cancer. GTV delineation is verified by a dedicated breast radiologist. To account for microscopic disease, the GTV is uniformly expanded by 2 cm to create the clinical target volume (CTV), while excluding the first 5 mm below the skin and the entire chest wall including the pectoral muscles, and not extending outside the breast tissue. For generating the planning target volumes (PTV), the GTV and CTV are expanded by 3 mm to obtain the planning target volumes PTVGTV and PTVCTV, respectively. The PTV is a margin to account for patients’ movements during treatment and setup uncertainties.

For MR-guided radiotherapy, intensity modulated radiotherapy (IMRT) technique will be used on the MRIdian (ViewRay, USA) or Elekta Unity (Elekta, Sweden). On the conventional linac, IMRT or volumetric modulated arc therapy (VMAT) techniques will be used. In a single fraction, two RT dose levels are concomitantly prescribed: 15 Gy to the PTVCTV and 20 Gy to the PTVGTV. Adequate target coverage is defined as a Dmean of the PTVGTV and PTVCTV of 99–101%, 98% or more of the PTVs receiving at least 95% of the prescribed dose and 2% or less of the PTVs receiving 107% of the prescribed dose, whilst respecting the organs at risk (OAR) doses (Table2). If optimal target volume cannot be achieved without exceeding the predefined dosimetrical constraints, the patient will be excluded from the study. In Fig. 3 an example of a single-dose PBI treatment plan is illustrated.

Table 2 Dose constraints for organs at risk in the ABLATIVE-2 trial
Fig. 3
figure 3

Dose distribution of single-dose ablative radiotherapy on MRIdian (Viewray, USA). Legend: The red isodose (20 Gy) represents the prescribed dose to the gross tumor volume (GTV). The green isodose (19 Gy) represents 95% of the prescribed dose to the GTV. The yellow isodose (15 Gy) represents the prescribed dose to the clinical target volume (CTV). The blue isodose (14.3 Gy) represents 95% of the prescribed dose to the CTV

Radiotherapy treatment delivery

The single-dose PBI will be delivered within three weeks following the planning MRI- and CT scan. On the conventional linacs and the MRIdian (ViewRay Inc., USA), MR-guided RT delivery will take place either with repeated breath-hold periods for patients with significant tumor movement or in free breathing when the tumor position is not affected by the breathing movement. On the Elekta Unity (Elekta, Sweden), treatment delivery will be performed using free-breathing. On both MR-linacs, online adaption of the treatment plan will be performed based on the MRI immediately before treatment delivery. Real-time MRI tumor tracking will be used on the MRIdian during the treatment procedure. On the conventional linacs, real-time position management and/or surface guidance will be used for patient tracking. The patient will fill out a questionnaire on comfort during the treatment procedure.

Follow-up after single-dose ablative treatment

Frequent clinical and radiological evaluation will be performed after single-dose PBI at 2 weeks, 3, 6, 9, and 12 months. Tumor response will be classified according to the ‘Response Evaluation Criteria in Solid Tumors’ guidelines [33]. Radiologic complete response on MRI is defined as the complete absence of pathologic contrast enhancement and complete absence of pathologic apparent diffusion coefficient reduction in the original tumor bed. Additionally, at baseline and during each follow-up consultation (i.e. at 2 weeks, 3, 6, 9, and 12 months) blood samples will be taken.

Patients with an indication for endocrine therapy will start this treatment following RT. The treating medical oncologist will monitor the endocrine treatment. If the surgical specimen shows any microscopic findings resulting in an indication for the start or change of adjuvant systemic therapy according to the Dutch national guidelines, patients will be treated accordingly [34].

Breast-conserving surgery

To assess the effect of RT on the breast tumor, BCS is performed at 12 months following RT. BCS will be performed ahead of time in case radiologic tumor progression (an increased size of contrast enhancement) is observed, or in case the MRI does not show rCR at 6 months following RT.

The surgical specimen is evaluated by a dedicated breast pathologist at the hospital where the surgery is performed. Viable tumor cells will be evaluated using hematoxylin and eosin staining and the activity of cytokeratin antibodies. Pathologic response will be categorized according to the European Society of Mastology (EUSOMA criteria).

  • 1. Complete pathologic response is defined as either no residual carcinoma or no residual invasive carcinoma but ductal carcinoma in situ (DCIS) may be present.

  • 2. Partial response to therapy

  • a. Near complete response is defined as minimal residual disease (<10% tumor cells)

  • b. Evidence of response (10-50% tumor cells)

  • c. >50% tumor cellularity remains evident with features of response present (e.g. fibrosis)

  • 3. No evidence of response

In addition, the proportion of patients with DCIS in the surgical specimen will be recorded. The surface of the excision specimen will be marked with Indian ink to evaluate surgical margins. Surgical margins will be described as minimal microscopic tumor-free margins of invasive and in situ carcinoma in millimeters (mm). This will always be performed in the direction of the nearest surgical margin. If tumor-positive margins are found, a radical re-excision needs to be performed.


Clinical consultations with the treating radiation oncologist including physical examination will be performed yearly from BCS to 5 years after single-dose RT, and every other year from 6 to 10 years. During the consultation, toxicity and cosmetic outcome will be assessed by the radiation oncologist (Fig. 1). Questionnaires on quality of life, distress, and cosmetic outcome questionnaires will be filled out by the patient. Digital photographs for objective evaluation of cosmetic outcome will also be taken at 3, 5, and 10 years after RT. As per standard of care, radiological follow-up will consist of yearly mammograms in the first 5 years. After 5 years, additional mammograms will be performed at 6, 8, and 10 years after RT.


The diagnostic biopsy, the surgical specimen, and blood samples will be preserved for 25 years at the Amsterdam UMC Central Biobank, location VUmc for future research in the field of breast cancer if patients give additional consent. To evaluate the radiation effect on gene expression in the breast tumor, additional consent for gene expression profiling is obtained. Since the tissue volume of the diagnostic biopsy is too little for gene expression profiling, 2–3 extra 14G tumor biopsies are taken after additional informed consent by the patient. RNA is easily degraded during the process of formalin fixation and a large variety exists due to different protocols used for fixation [35, 36]. Therefore, fresh frozen biopsies are used for gene expression profiling with RNA.

Ethical aspects

This study is conducted according to the Declaration of Helsinki (Fortaleza, Brazil, October 2013) and the Dutch Medical Research Involving Human Subjects Act ( The study protocol has been approved by the Medical Research Ethic Committee of the Amsterdam UMC, location VUmc (NL77000.029.21), and has been registered at an international trial registry ( NCT05350722). The study has been approved by the Institutional Review Board of each participating center. After a written and oral explanation of the study, all patients are required to give written informed consent before inclusion.

Quality assurance

To assure the quality and validity of the research data, an independent qualified monitor will carry out study monitoring centrally at the Clinical Monitoring Center of the Amsterdam UMC, location VUmc. The monitoring will be performed according to national guidelines on quality control for Dutch University Medical Centers [37].

Statistical analysis

Sample size calculation is performed based on the primary endpoint: the rate of pathologic complete response. We expect that 40% of our patients will achieve pathologic complete response 12 months after high-dose single fraction PBI. The sample size calculation is performed using the Wilson method for the calculation of different 95% confidence intervals (CI) for proposed sample sizes. A sample size of 100 patients would produce an acceptable 95% CI ranging from 30.9% to 49.8% while maintaining practical applicability.

The proportion of patients with pCR 12 months after RT will be evaluated and a 95% CI will be calculated. Regarding the secondary outcome, radiologic response, the negative and positive predictive value of radiologic response for pCR with 95% CIs will be calculated for all intervals between RT and BCS. Patient-reported and cosmetic outcomes will be analyzed in a linear mixed model for repeated measures. Radiation- and surgery-induced toxicity, local, regional and distant relapse rates, disease-free and overall survival will be reported using descriptive statistics. Kaplan–Meier method will be used to quantify disease-free and overall survival. The natural variability of the response markers will be evaluated for all accrued patients, exploring overlap in variance among the different response markers, and if applicable studying the reproducibility of the potential response markers.


The ABLATIVE-2 study is a continuation of the ABLATIVE study (NCT02316561) in which 36 patients were treated with a single ablative RT dose and BCS at 6 or 8 months following RT. This study showed that single-dose pre-operative PBI was technically and clinically feasible in patients with low-risk breast cancer [21]. The pCR rate after 8 months between RT and BCS seemed to be higher than after 6 months (48% vs. 33%). Therefore, in the current ABLATIVE-2 design, the interval between RT and BCS is prolonged to 12 months. In addition, the predictive value of quantitative MRI parameters and immunological markers, and potential biomarkers in blood and tumor tissue for pCR will be evaluated.

Over the last decades, clinical research has been focused on personalized treatment aiming to de-escalate breast cancer treatment. In patients with early-stage breast cancer, BCS followed by WBI resulted in equivalent recurrence rates and overall survival compared with mastectomy [5, 38, 39]. In addition, axillary RT has replaced axillary lymph node dissection in patients with a tumor-positive sentinel node [40]. Genomic tools are utilized to identify low-risk patients with no benefit from chemotherapy [41, 42]. Irradiation times of breast cancer patients have been shortened with (ultra-) hypofractionated radiation schedules and treatment volumes have been reduced with accelerated PBI instead of whole breast irradiation in low-risk patients [11, 12, 43,44,45,46]. Thus, breast cancer treatment has become increasingly patient-tailored over the years.

Improved diagnostic modalities and treatment have led to a 15% decline in breast cancer mortality rates in Europe between 2002 and 2012 [47]. However, breast cancer patients seem to prefer treatments that result in less functional disability and pain over progression-free survival months [48]. As such, studies focusing on reducing radiation- and surgery-induced toxicity and improving the cosmetic outcome of personalized breast cancer treatment are increasingly performed. The introduction of pre-operative PBI has been gaining interest and has the potential to lead to a paradigm shift in the treatment of low-risk patients [17,18,19,20,21,22,23, 49]. PBI in the pre-operative setting has several advantages over post-operative treatment. Pre-operative tumor delineation is more accurate and leads to a reduced volume of irradiated healthy breast tissue, while still adhering to oncologically safe margins [13,14,15]. Precise irradiation could lead to milder toxicity and better cosmetic outcome [50]. The tumoricidal effect of irradiation can lead to tumor downstaging and preservation of breast tissue during surgical excision. In the ABLATIVE study an higher pCR rate of 42% was observed after a longer interval between pre-operative radiotherapy and surgery of 6 to 8 months [21]. In the PAPBI trial, 133 patients were treated with pre-operative PBI. Seventy-eight patients were treated with 40 Gy in 10 fractions in 2 weeks and 55 patients with 30 Gy in 5 fractions in 1 week [19]. BCS was performed 6 weeks after pre-operative PBI and a pCR rate of 10% was reported. IBTR was found in 3% of the patients after a median follow-up of 5 years and overall survival was 97%. The study by Nichols et al. included 27 patients, who received pre-operative PBI 10 × 3.85 Gy in 1 week [20]. After 3 weeks, pCR was achieved in 15% of the patients. Toxicity was mainly mild in this study and good to excellent cosmetic outcome was reported by 78% of the patients. Similar results were found in the ROCK trial. Twenty-two patients were treated with a pre-operative single-dose of 21 Gy using the Cyberknife® and BCS after 2 weeks [24]. Two patients (9%) experienced a pCR and no toxicity higher than grade 2 was reported. Cosmetic outcomes on the other hand were rated as good or excellent by 62% of the physicians. The SPORT-DS trial evaluated a pre-operative single-dose of 20 Gy and another retrospective cohort study evaluated a schedule with multiple fractions (3 × 9.5 Gy) followed by BCS after 3 and 6–8 weeks, respectively [17, 18]. These studies did not report a pCR in any of the patients, despite similar interval durations between PBI and BCS compared to the previously described studies. This difference could be explained by the small sample sizes.

The post-operative complication rate of BCS after pre-operative PBI is 14–17% [19, 21]. These complications include hemorrhage and wound infection. Analysis of 648 patients in the Cambridge IMRT trial, in which patients were treated with BCS followed by WBI, showed a post-operative infection rate of 19.7% and a hematoma rate of 7.9% [51]. Results of the study have proven that the presence of seroma is associated with post-operative infection and hemorrhage [52]. The FOCUS cohort study collected data on all consecutive patients aged 65 years and older with breast cancer in the Netherlands between 1997 and 2004 [53]. The post-operative complication rate for patients treated with BCS was 14%, which is similar to the patients treated with pre-operative PBI. In the ABLATIVE-2 trial, patients will have 12 months of recovery time until BCS is performed. So the negative effect of RT on the incidence of post-operative complications is expected to be minimalized.

Long-term outcomes of pre-operative PBI are awaited with the continuation of follow-up in these studies [17, 23, 54]. Continuation of patient accrual in the SPORT-DS trial will provide more information on tumor response rate in a larger study population (Table 3) [17]. The SIGNAL-2 trial (NCT02212860) will prolong the interval between RT and BCS from 1 to 3 weeks [22]. Based on the positive results of the previous phase I trial of Horton et al., a larger patient cohort will be treated with a single dose of 21 Gy at Duke University (NCT02482376) [23]. The optimal ablative dose has not yet been established, thus phase I dose-escalation trials (NCT04679454, NCT04040569) are recruiting patients to identify the maximum tolerated dose. The ABLATIVE-2 study is, to the best of our knowledge, the first study to evaluate the effect of pre-operative single-dose PBI after a longer interval, i.e. 12 months.

Table 3 Summary of the clinical trial regarding pre-operative partial breast irradiation

The prediction of pCR using MRI will be challenging in the current study design. MRI will be performed at different time points after RT to evaluate tumor response. The MRI at 2 weeks in particular aims to identify early radiation effects. The parameter extraction from an MRI contains substantial variability across patients [55]. Therefore, reference objects, image acquisition protocols, and software for image data analysis need to be implemented. Hence, study results will have to identify other radiological predictors or tumor response markers in blood or tumor tissue to select good responders to RT.

A meta-analysis showed that the detection rates of ctDNA in blood samples of patients with early-stage breast cancer at baseline range between 23–100% [31]. Most studies included patients with triple-negative breast cancer, who have a higher ctDNA detection rate than patients with an ER + tumor [31, 56,57,58]. In patients with ER + early-stage breast cancer, ctDNA was detected in 24% of the patients (n = 51) [58]. However, the median ctDNA level, measured using personalized digital polymerase chain reaction assays, was 0 copies/ml in patients with a clinical T1 tumor. The detection of ctDNA in patients with early-stage breast cancer increases with deep sequencing using large gene panels. Zhang et al. prospectively collected plasma samples of 102 early-stage breast cancer patients and reached a positive detection rate of 74% (49/66) [56]. For patients with a clinical T1 tumor, the detection rate was 56%. Patients with a higher number (40–90%) of TILs were more likely to have ctDNA detection (92%) compared to patients with a low number (< 10%) of TILs (60%).

Similar to ctDNA detection, TILs levels are higher in triple-negative and HER2 + tumors [59, 60]. Still, in patients with luminal A breast cancer TILs have a prognostic value [61, 62]. The SweBCG91cRT trial has shown that patients with a Luminal A tumor and a low TILs score have a 51% reduced risk of IBTR when treated with post-operative RT compared to no post-operative RT [61]. In the ABLATIVE study, six to eight months after single-dose pre-operative PBI, a decrease of CD3, CD4, and CD8 TILs was found in tumor tissue [29]. However, no differences in TILs levels were found in responders vs. non-responders. Due to low TILs levels in luminal A tumors and subtle differences after treatment, analyzing a larger patient cohort will be necessary to predict pCR after single-dose pre-operative PBI using TILs.

Post-operative endocrine therapy is the standard of care for patients with an indication according to the Dutch guidelines. As surgery is scheduled 6 to 12 months after RT, endocrine therapy is allowed after RT (and before surgery) in this trial, despite possible tumor downstaging. The ABLATIVE-2 study has intensive MRI follow-up to monitor tumor response after pre-operative PBI and allows safe prolongation of the interval to BCS. In prospect, the number of MRIs could be reduced in case no disease progression is observed during the monitoring phase in this trial. In addition, the extensive diagnostic workup including a sentinel node procedure could be de-escalated, if favorable oncological outcomes are found in the current SOUND trial (Sentinel Node vs Observation After Axillary Ultrasound, NCT02167490) of the European Institute of Oncology in which the omission of the sentinel node procedure in clinically node-negative cT1 breast cancer patients undergoing BCS is investigated. This will make the clinical implementation of pre-operative single-dose PBI more practical. Nonetheless, MR-guided RT delivery is not common practice in most hospitals. The use of conventional and MR-linacs from different manufacturers could influence clinical outcomes of radiation treatment due to variations in the treatment protocols of the machines. The MR-linac provides an online adaptive workflow with good visibility of the breast tumor on MRI. This allows more precise treatment delivery and irradiation of smaller non-intended breast volumes reducing radiation-induced toxicity.

The ABLATIVE-2 trial is a multicenter prospective trial and contributes to the advancement of tailored breast cancer treatment with pre-operative single-fraction PBI in patients with low-risk breast cancer. If tumor response markers in blood or tumor tissue and radiological parameters are identified to successfully predict pCR in future patients, BCS could potentially be omitted in future low-risk patients. When a patient does not reach pCR after pre-operative single-fraction PBI, downstaging of the tumor could reduce excision volumes of healthy breast tissue and the number of RT fractions could be reduced to one single dose instead of the post-operative standard schedule of multi-fractionated RT for patients with early-stage breast cancer [43]. This could result in an overall reduction of treatment burden for patients and improve logistic challenges in healthcare.

Availability of data and materials

Not applicable – data collection is still ongoing in this trial.



Breast conserving surgery


Whole breast irradiation


Ipsilateral breast tumor recurrence


Partial breast irradiation


American Society of Radiation Oncology


European Society of Radiation Oncology




Pathologic complete response


Radiologic complete response


Positive predictive value


Negative predictive value


Tumor-infiltrating lymphocytes


University Medical Centre


Vrije Universiteit Medical Centre


European Organization for Research and Treatment of Cancer core-30 questionnaire


European Organization for Research and Treatment of Cancer breast cancer-specific questionnaire


Hospital Anxiety and Depression Scale


Linear accelerator


Gross Tumor Volume


Clinical Target Volume


Planning Target Volume


Intensity modulated radiotherapy


Volumetric modulated arc therapy


Organs at risk


European Society of Mastology


Ductal carcinoma in situ




Confidence Interval


  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33.

    Article  PubMed  Google Scholar 

  3. Ward ZJ, Atun R, Hricak H, Asante K, McGinty G, Sutton EJ, et al. The impact of scaling up access to treatment and imaging modalities on global disparities in breast cancer survival: a simulation-based analysis. Lancet Oncol. 2021;22(9):1301–11.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363–85.

    Article  PubMed  Google Scholar 

  5. van Dongen JA, Voogd AC, Fentiman IS, Legrand C, Sylvester RJ, Tong D, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst. 2000;92(14):1143–50.

    Article  PubMed  Google Scholar 

  6. Early Breast Cancer Trialists' Collaborative G, Darby S, McGale P, Correa C, Taylor C, Arriagada R, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804):1707–16.

  7. Fisher ER, Anderson S, Redmond C, Fisher B. Ipsilateral breast tumor recurrence and survival following lumpectomy and irradiation: pathological findings from NSABP protocol B-06. Semin Surg Oncol. 1992;8(3):161–6.

    CAS  PubMed  Google Scholar 

  8. Shah C, Jia X, Hobbs BP, Tendulkar RD, Sittenfeld SMC, Al-Hilli Z, et al. Outcomes with partial breast irradiation vs. whole breast irradiation: a meta-analysis.  Ann Surg Oncol. 2021;28(9):4985–94.

  9. Correa C, Harris EE, Leonardi MC, Smith BD, Taghian AG, Thompson AM, et al. Accelerated partial breast irradiation: executive summary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol. 2017;7(2):73–9.

    Article  PubMed  Google Scholar 

  10. Polgar C, Van Limbergen E, Potter R, Kovacs G, Polo A, Lyczek J, et al. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiother Oncol. 2010;94(3):264–73.

    Article  PubMed  Google Scholar 

  11. Meattini I, Marrazzo L, Saieva C, Desideri I, Scotti V, Simontacchi G, et al. Accelerated partial-breast irradiation compared with whole-breast irradiation for early breast cancer: long-term results of the randomized phase III APBI-IMRT-florence trial. J Clin Oncol. 2020;38(35):4175–83.

    Article  PubMed  Google Scholar 

  12. Coles CE, Griffin CL, Kirby AM, Titley J, Agrawal RK, Alhasso A, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet. 2017;390(10099):1048–60.

    Article  PubMed  PubMed Central  Google Scholar 

  13. van der Leij F, Bosma SC, van de Vijver MJ, Wesseling J, Vreeswijk S, Rivera S, et al. First results of the preoperative accelerated partial breast irradiation (PAPBI) trial. Radiother Oncol. 2015;114(3):322–7.

    Article  PubMed  Google Scholar 

  14. den Hartogh MD, Philippens ME, van Dam IE, Kleynen CE, Tersteeg RJ, Pijnappel RM, et al. MRI and CT imaging for preoperative target volume delineation in breast-conserving therapy. Radiat Oncol. 2014;9:63.

    Article  Google Scholar 

  15. Nichols EM, Dhople AA, Mohiuddin MM, Flannery TW, Yu CX, Regine WF. Comparative analysis of the post-lumpectomy target volume versus the use of pre-lumpectomy tumor volume for early-stage breast cancer: implications for the future. Int J Radiat Oncol Biol Phys. 2010;77(1):197–202.

    Article  PubMed  Google Scholar 

  16. Leonard KL, Wazer DE, Listo M, Hepel JT. Mammographically guided noninvasive breast brachytherapy: Preoperative partial breast radiotherapy markedly improves targeting accuracy and decreases irradiated volume. Brachytherapy. 2021;20(2):339–44.

    Article  PubMed  Google Scholar 

  17. Tiberi D, Vavassis P, Nguyen D, Guilbert MC, Simon-Cloutier A, Dube P, et al. Tumour response 3 months after neoadjuvant single-fraction radiotherapy for low-risk breast cancer. Curr Oncol. 2020;27(3):155–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Weinfurtner RJ, Raghunand N, Stringfield O, Abdalah M, Niell BL, Ataya D, et al. MRI response to pre-operative Stereotactic Ablative Body Radiotherapy (SABR) in early stage ER/PR+ HER2- breast cancer correlates with surgical pathology tumor bed cellularity. Clin Breast Cancer. 2022;22(2):e214–23.

    Article  CAS  PubMed  Google Scholar 

  19. Bosma SCJ, Leij F, Vreeswijk S, Maaker M, Wesseling J, Vijver MV, et al. Five-year results of the Preoperative Accelerated Partial Breast Irradiation (PAPBI) Trial. Int J Radiat Oncol Biol Phys. 2020;106(5):958–67.

    Article  PubMed  Google Scholar 

  20. Nichols E, Kesmodel SB, Bellavance E, Drogula C, Tkaczuk K, Cohen RJ, et al. Preoperative accelerated partial breast irradiation for early-stage breast cancer: preliminary results of a prospective, phase 2 trial. Int J Radiat Oncol Biol Phys. 2017;97(4):747–53.

    Article  PubMed  Google Scholar 

  21. Vasmel JE, Charaghvandi RK, Houweling AC, Philippens MEP, van Asselen B, Vreuls CPH, et al. Tumor response after neoadjuvant magnetic resonance guided single ablative dose partial breast irradiation. Int J Radiat Oncol Biol Phys. 2020;106(4):821–9.

    Article  CAS  PubMed  Google Scholar 

  22. Guidolin K, Lock M, Vogt K, McClure JA, Winick-Ng J, Vinden C, et al. Recurrence and mortality after breast-conserving surgery without radiation. Curr Oncol. 2019;26(6):380–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Horton JK, Blitzblau RC, Yoo S, Geradts J, Chang Z, Baker JA, et al. Preoperative single-fraction partial breast radiation therapy: a novel phase 1, dose-escalation protocol with radiation response biomarkers. Int J Radiat Oncol Biol Phys. 2015;92(4):846–55.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Meattini I, Francolini G, Di Cataldo V, Visani L, Becherini C, Scoccimarro E, et al. Preoperative robotic radiosurgery for early breast cancer: results of the phase II ROCK trial (NCT03520894). Clin Transl Radiat Oncol. 2022;37:94–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bosma SCJ, Hoogstraat M, van der Leij F, de Maaker M, Wesseling J, Lips E, et al. Response to preoperative radiation therapy in relation to gene expression patterns in breast cancer patients. Int J Radiat Oncol Biol Phys. 2020;106(1):174–81.

    Article  CAS  PubMed  Google Scholar 

  26. Reig B, Lewin AA, Du L, Heacock L, Toth HK, Heller SL, et al. Breast MRI for evaluation of response to neoadjuvant therapy. Radiographics. 2021;41(3):665–79.

    Article  PubMed  Google Scholar 

  27. Lobbes MB, Prevos R, Smidt M, Tjan-Heijnen VC, van Goethem M, Schipper R, et al. The role of magnetic resonance imaging in assessing residual disease and pathologic complete response in breast cancer patients receiving neoadjuvant chemotherapy: a systematic review. Insights Imaging. 2013;4(2):163–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bosma SCJ, van der Leij F, Elkhuizen PHM, Vreeswijk S, Loo CE, Vogel WV, et al. Evaluation of early response to Preoperative Accelerated Partial Breast Irradiation (PAPBI) by histopathology, magnetic resonance imaging, and 18F-fluorodexoyglucose Positron Emission Tomography/Computed Tomography (FDG PET/CT). Int J Radiat Oncol Biol Phys. 2021;110(4):1151–8.

    Article  PubMed  Google Scholar 

  29. Vasmel JE, Vreuls CPH, Manson QF, Charaghvandi RK, van Gorp J, van Leeuwen AMG, et al. Tumor-infiltrating lymphocytes in low-risk patients with breast cancer treated with single-dose preoperative partial breast irradiation. Int J Radiat Oncol Biol Phys. 2021;109(5):1325–31.

    Article  PubMed  Google Scholar 

  30. Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19(1):40–50.

    Article  PubMed  Google Scholar 

  31. Papakonstantinou A, Gonzalez NS, Pimentel I, Sunol A, Zamora E, Ortiz C, et al. Prognostic value of ctDNA detection in patients with early breast cancer undergoing neoadjuvant therapy: a systematic review and meta-analysis. Cancer Treat Rev. 2022;104: 102362.

    Article  CAS  PubMed  Google Scholar 

  32. Common Terminology Criteria for Adverse Events (CTCAE) Version 5. National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. https:/​/ctep.​​protocoldevelopment/​electronic_applications/​docs/​CTCAE_v5_Quick_Reference_5x7.​pdf Accessed 16 May 2022.

  33. RECIST, the official site of the RECIST Working Group guidelines. (2009). Accessed 16 May 2022.

  34. Guideline NABON. Treatment of breast cancer. Richtlijn 'Behandeling van het Mammacarcinoom'. 2017. Accessed 12 May 2022.

  35. Jones W, Greytak S, Odeh H, Guan P, Powers J, Bavarva J, et al. Deleterious effects of formalin-fixation and delays to fixation on RNA and miRNA-Seq profiles. Sci Rep. 2019;9(1):6980.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gaffney EF, Riegman PH, Grizzle WE, Watson PH. Factors that drive the increasing use of FFPE tissue in basic and translational cancer research. Biotech Histochem. 2018;93(5):373–86.

    Article  CAS  PubMed  Google Scholar 

  37. Kwaliteitsborging mensgebonden onderzoek: Nederlandse Federatie van Universitair Medische Centra. (2020). Accessed 12 May 2022.

  38. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347(16):1233–41.

    Article  PubMed  Google Scholar 

  39. Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347(16):1227–32.

    Article  PubMed  Google Scholar 

  40. Bartels SAL, Donker M, Poncet C, Sauvé N, Straver ME, Velde CJHvd, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981–22023 AMAROS trial. J Clin Oncol.0(0):JCO.22.01565.

  41. Lopes Cardozo JMN, Drukker CA, Rutgers EJT, Schmidt MK, Glas AM, Witteveen A, et al. Outcome of patients with an ultralow-risk 70-gene signature in the MINDACT Trial. J Clin Oncol. 2022;40(12):1335–45.

    Article  CAS  PubMed  Google Scholar 

  42. Soliman H, Shah V, Srkalovic G, Mahtani R, Levine E, Mavromatis B, et al. MammaPrint guides treatment decisions in breast Cancer: results of the IMPACt trial. BMC Cancer. 2020;20(1):81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Murray Brunt A, Haviland JS, Wheatley DA, Sydenham MA, Alhasso A, Bloomfield DJ, et al. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet. 2020;395(10237):1613–26.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Agrawal RK, Alhasso A, Barrett-Lee PJ, Bliss JM, Bliss P, Bloomfield D, et al. First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015). Radiother Oncol. 2011;100(1):93–100.

    Article  PubMed  Google Scholar 

  45. Whelan TJ, Julian JA, Berrang TS, Kim DH, Germain I, Nichol AM, et al. External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial. Lancet. 2019;394(10215):2165–72.

    Article  PubMed  Google Scholar 

  46. Vicini FA, Cecchini RS, White JR, Arthur DW, Julian TB, Rabinovitch RA, et al. Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial. Lancet. 2019;394(10215):2155–64.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Carioli G, Malvezzi M, Rodriguez T, Bertuccio P, Negri E, La Vecchia C. Trends and predictions to 2020 in breast cancer mortality in Europe. The Breast. 2017;36:89–95.

    Article  PubMed  Google Scholar 

  48. Stamuli E, Corry S, Ross D, Konstantopoulou T, Texeira L, Avouac B, et al. Patient preferences for breast cancer treatments: a discrete choice experiment in France, Ireland, Poland and Spain. Future Oncol. 2022;18(9):1115–32.

    Article  CAS  PubMed  Google Scholar 

  49. Vanderwalde NA, Jones EL, Kimple RJ, Moore DT, Klauber-Demore N, Sartor CI, et al. Phase 2 study of pre-excision single-dose intraoperative radiation therapy for early-stage breast cancers: six-year update with application of the ASTRO accelerated partial breast irradiation consensus statement criteria. Cancer. 2013;119(9):1736–43.

    Article  PubMed  Google Scholar 

  50. Hepel JT, Tokita M, MacAusland SG, Evans SB, Hiatt JR, Price LL, et al. Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2009;75(5):1290–6.

    Article  PubMed  Google Scholar 

  51. Mukesh MB, Barnett G, Cumming J, Wilkinson JS, Moody AM, Wilson C, et al. Association of breast tumour bed seroma with post-operative complications and late normal tissue toxicity: results from the Cambridge Breast IMRT trial. Eur J Surg Oncol. 2012;38(10):918–24.

    Article  CAS  PubMed  Google Scholar 

  52. Mukesh M, Harris E, Jena R, Evans P, Coles C. Relationship between irradiated breast volume and late normal tissue complications: a systematic review. Radiother Oncol. 2012;104(1):1–10.

    Article  PubMed  Google Scholar 

  53. de Glas NA, Kiderlen M, Bastiaannet E, de Craen AJM, van de Water W, van de Velde CJH. Postoperative complications and survival of elderly breast cancer patients: a FOCUS study analysis. Breast Cancer Res Treat. 2013;138(2):561–9.

    Article  CAS  PubMed  Google Scholar 

  54. Guidolin K, Yaremko B, Lynn K, Gaede S, Kornecki A, Muscedere G, et al. Stereotactic image-guided neoadjuvant ablative single-dose radiation, then lumpectomy, for early breast cancer: the signal prospective single-arm trial of single-dose radiation therapy. Curr Oncol. 2019;26(3):334–40.

    Article  Google Scholar 

  55. Kim H. Variability in Quantitative DCE-MRI: sources and solutions. J Nat Sci. 2018;4(1): e484.

    PubMed  PubMed Central  Google Scholar 

  56. Zhang X, Zhao W, Wei W, You Z, Ou X, Sun M, et al. Parallel analyses of somatic mutations in plasma circulating tumor DNA (ctDNA) and matched tumor tissues in early-stage breast cancer. Clin Cancer Res. 2019;25(21):6546–53.

    Article  CAS  PubMed  Google Scholar 

  57. Li S, Lai H, Liu J, Liu Y, Jin L, Li Y, et al. Circulating tumor DNA predicts the response and prognosis in patients with early breast cancer receiving neoadjuvant chemotherapy. JCO Precis Oncol. 2020;4:244–57.

    Article  Google Scholar 

  58. Garcia-Murillas I, Chopra N, Comino-Méndez I, Beaney M, Tovey H, Cutts RJ, et al. Assessment of molecular relapse detection in early-stage breast cancer. JAMA Oncol. 2019;5(10):1473–8.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Stenmark Tullberg A, Puttonen HAJ, Sjostrom M, Holmberg E, Chang SL, Feng FY, et al. Immune infiltrate in the primary tumor predicts effect of adjuvant radiotherapy in breast cancer; results from the randomized SweBCG91RT trial. Clin Cancer Res. 2021;27(3):749–58.

    Article  PubMed  Google Scholar 

  60. Schiza A, Thurfjell V, Stenmark Tullberg A, Olofsson H, Lindberg A, Holmberg E, et al. Tumour-infiltrating lymphocytes add prognostic information for patients with low-risk DCIS: findings from the SweDCIS randomised radiotherapy trial. Eur J Cancer. 2022;168:128–37.

    Article  CAS  PubMed  Google Scholar 

  61. Kovacs A, Stenmark Tullberg A, Werner Ronnerman E, Holmberg E, Hartman L, Sjostrom M, et al. Effect of radiotherapy after breast-conserving surgery depending on the presence of tumor-infiltrating lymphocytes: a long-term follow-up of the SweBCG91RT randomized trial. J Clin Oncol. 2019;37(14):1179–87.

    Article  CAS  PubMed  Google Scholar 

  62. Millar E, Browne L, Slapetova I, Shang F, Ren Y, Bradshaw R, et al. TILs immunophenotype in breast cancer predicts local failure and overall survival: analysis in a large radiotherapy trial with long-term follow-up. Cancers (Basel). 2020;12(9):2365.

Download references


We acknowledge F.J. Lagerwaard for his input for this manuscript and enabling treatment of breast cancer patients on MRIdian (Viewray, USA)


This study is funded by KWF Dutch Cancer Society (grant number: 12138) who has no role in collection, analysis, and interpretation of data or in writing the manuscripts.

Author information

Authors and Affiliations



HJGDB, ALO, KMD, SDV, NB, PM, ZK, MAP, LS, EB, IRHMK, CWMHO, PGW, HJMM, GMPD, VT, FM, and BJS set up the study design and/or study protocol. YAC, ALO, KMD, SDV, LD, SV, MAP, EB, GMPD, PGW, HJMM and HJGDB are currently involved in study implementation. YAC, HJGDB, ALO and SDV wrote the first draft of the manuscript. ALO prepared Fig. 1. SV prepared Fig. 3. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Yasmin A. Civil.

Ethics declarations

Ethics approval and consent to participate

Ethical committee approval of the Amsterdam University Medical Centre, location Vrije Universiteit Medical Centre (reference number NL77000.029.21) was obtained for the ABLATIVE-2 study. The study has been approved by the institutional review board of Amsterdam University Medical Centre. The study has also been approved by the institutional review board of Radboud University Medical Centre in Nijmegen. All methods are carried out in accordance with relevant guidelines and regulations. All participants will sign an informed consent. Informed consent was also required from a healthy volunteer who agreed to use the MRI-image for creating radiotherapy treatment plans and for publication.

Consent for publication

Consent was obtained from the healthy volunteer to use the MR-image for publication.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Civil, Y.A., Oei, A.L., Duvivier, K.M. et al. Prediction of pathologic complete response after single-dose MR-guided partial breast irradiation in low-risk breast cancer patients: the ABLATIVE-2 trial—a study protocol. BMC Cancer 23, 419 (2023).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: